Use of oligosaccharides for the treatment of pruritus cutaneus associated with renal failure

ABSTRACT

A pharmaceutical agent for improvement in pruritus cutaneus associated with renal failure and/or for the treatment of renal failure and/or its complications containing as an effective ingredient oligosaccharide or oligosaccharides such as, but not limited to fructo-oligosaccharide, galacto-oligosaccharide, isomalto-oligosaccharide, malto-oligosaccharide, lacto-sucrose and/or xylo-oligosaccharide, in particular, lactulose, rhamnose and lactitol.

TECHNICAL FIELD

This invention relates to a new pharmaceutical composition foralleviation of various syndromes, in particular pruritus cutaneus,characteristic to renal failure and hemodialysis patients.

BACKGROUND ART

Among the countries all over the world, the hemodialysis therapy is mostwidely practiced in Japan. This therapy over an extended time, however,induces various serious problems. The hemodialysis therapy for a longtime, for example, causes the onset of complications such ascardiovascular disorder, anemia, abnormal bone metabolism, dysbolism,and/or immunodeficiency. In addition, it is said that 60-80% of thehemodialysis patients suffer from pruritus cutaneus. Although prurituscutaneus itself does not impose direct threatening on the life of thepatients, its persistent and chronic torment, night and day, isunbearable to the patients, both physically and mentally. From the viewpoint of the maintenance and improvement in the quality of life,pruritus cutaneus is now a big problem in the treatment of the patients.

As a possible cause of pruritus cutaneus, 1. stimulation of the nerveending by a certain substance accumulated in the blood by renal failure,2. a decline in the pruritus threshold value due to change in the pHvalue, etc., or 3. abnormal secretion by the skin glands such assebaceous glands and sweat glands, is suspected but it Is not yet clearwhat is responsible for it. For its treatment, antihistaminic agent isgenerally administered but it has limitation in its efficacy. Besides,due to its side effects like drowsiness, vertigo or generalized malaise,its administration must be discontinued in many cases. In addition,anti-allergic agent, adrenocortical agent or tranquilizer isadministered but no agent alone can relieve the patients from thetorment and establishment of an effective therapy has been expected.

DISCLOSURE OF INVENTION

The applicants of this invention have been conducting their researchfocusing on alleviation of pruritus cutaneus, among other complications,developed in renal failure patients treated with the hemodialysistherapy for a long time.

As the most potential substances that induce pruritus, recent studiessuggest accumulation of uremic toxins and active oxygen. Since theremoval rate of those substances by hemodialysis is very low, theapplicants of this invention conducted clinical trials on the assumptionthat suppression of production of uremic toxins would prompt improvementin pruritus cutaneus.

As a result, administration of lactulose for one or two months decreasedsignificantly toxic amino acid metabolites responsible for aggravationof uremia such as guanidino compounds like methylguanidine andguanidinosuccinic acid, indolacetic acid, p-cresol and declinedmethylguadinine/creatinine that is considered to be a physical activeoxygen marker of the renal hemodialysis patients. The applicants of thisinvention found the correlation between the decrease in those uremictoxins and decline in the active oxygen marker and improvement inpruritus cutaneus, thus, completed this invention. This inventionprovides a pharmaceutical agent containing one, two or more kind orkinds of oligosaccharide or oligosaccharides as an effective ingredientfor improvement in pruritus cutaneus associated with renal failure.

BEST MODE FOR CARRYING OUT THE INVENTION

Details of the invention are described below.

In addition to lactulose which has long been known as a growth factor ofbifidobacteria, there have been found various kinds oligosaccharide thatshow the same effect. It is known that oligosaccharide such as, but notlimited to, fructo-oligosaccharide, galactooligosaccharide,lacto-sucrose, maltooligosaccharide and xylooligosaccharide growremarkably bifidobacteria in stool and reduce significantly toxicsubstances like ammonia, amine phenol and cresol in it. There has,however, been no report made so far on the effect of sucholigosaccharide on the treatment of renal failure, in particular, onalleviation of pruritus. It is well known that ammonia is produced bydeamination of part of protein or amino acids in the intestine by theintestinal bacteria and decomposition of lactulose by bifidobacteria orother intestinal bacteria in the large intestine help promote theproduction of organic acids like lactic acid, acetic acid, etc. which inturn decrease the pH value and inhibit absorption of ammonia. On accountof this effect, lactulose has been used for the treatment ofhyperammonemia. It is also known that administration of lactulosesuppresses production of amines like phenol, skatole and indole in theintestine and promotes absorption of calcium in the small intestine.Nonetheless, the effect of lactulose on renal failure or itscomplications, especially pruritus cutaneus, has not been recognized.Renal hypofunction elicits uremic syndrome like insomnia, cephalea,vomiturition, renal anemia, hypertension and edema and they are treatedwith hemodialysis when they are not improved by the conservativetreatment. As substances called uremic toxins that accumulate in theuremic patients and exacerbate the disease such as β2-microglobulin,guanidine compounds, glycated proteins, indole compounds and phenolcompounds have been reported. Removal of those toxins by hemodialysis,however, is not sufficient and can not necessarily mitigate prurituscutaneus.

As the frequency of complications that develop in the patients treatedwith the hemodialysis treatment over a long period of time,cardiovascular complications are 50-60% and highest and cardiac failureis the highest cause of death. As complications that seriously affectthe daily life of the renal failure patients, there are renalosteodystrophia, dialysis amyloidosis, anemia and pruritus cutaneus. Apharmaceutical agent under this invention is, among other complicationsassociated with renal failure, most effective on alleviation of prurituscutaneus. The patients treated with the hemodialysis therapy are heldunder various diet restrictions and are restricted to ingest salt,water, protein and potassium. Due to restriction of diet, many of thehemodialysis patients suffer from constipation or have difficulty inexcretion.

The oligosaccharides in this invention activate intestinal peristalsisby promoting production of organic acids and improve excretion bysoftening stool. Furthermore, the oligosaccharides under this inventionincrease intestinal hydration by enhancing the intestinal osmoticpressure, thus enable smooth excretion. The oligosaccharide oroligosaccharides for a pharmaceutical agent under this invention for thetreatment of pruritus cutaneus associated with renal failure and/orrenal failure and its complications are a general term ofoligosaccharide or oligosaccharides having 2 to about 10 monosaccharidesglycosidically bonded and, according to the number of monosaccharidesbonded, are classified as disaccharide, trisaccharide, tetrasaccharide,etc. In this invention, one, two or more kinds of oligosaccharides suchas, but not limited to, fructooligosaccharide, galactooligosaccharide,isomaltooligosaccharide, maltooligosaccharide, lactosucrose and/orxylooligosaccharide used to achieve the purpose of this invention.Desirable oligosaccharides are disaccharides like, but not limited to,lactulose, trehalose, rhamnose and lactitol. Among thoseoligosaccharides, lactulose, in particular, is desirable.

Specifically, there is no limitation in the method of administration ofthe pharmaceutical agent under this invention for the treatment of renalfailure, mitigation of pruritus cutaneus and/or improvement in laxation,but oral administration is desirable. Those saccharide or saccharidesare supplied in crystal, amorphous powder, or syrup and can beadministered to the patients in any form of pharmaceutical preparationlike, but not limited to, granule, tablet, powder and syrup In such apharmaceutical preparation, filler, extender, disintegrator, hemuctant,bonding agent and/or lubricant normally used can be added as required.

A daily dose of the pharmaceutical agent in this invention is, as ananhydride, in the range of 1 gram to 60 grams depending upon age, sex,body weight and symptom of the patients and normally 1 gram to 30 gramsare preferred.

Example of Pharmaceutical Preparation

    ______________________________________                                        Lactulose           50 mg                                                     Starch             116 mg                                                     Glyceric fatty acid ester                                                                         30 mg                                                     Cellulose           2 mg                                                      Silicon oxide       2 mg                                                      Total              200 mg                                                     ______________________________________                                    

Detailed examples of this invention are described hereunder but they inno way limit the scope of this invention.

Example 1

A daily dose of 3 mg was administered orally to the healthy subjectsaged 18 to 23 (male 5 and female 3) for 2 weeks and their stool waschronologically collected for the determination of ammonia, phenol,cresol, indole and skatole. Table 1 shows the results.

                  TABLE 1                                                         ______________________________________                                        Effect of lactulose on concentration of toxic                                 substances in stool                                                                                (μg/1 g of stool)                                                          Day 7 after end of                                              Day 0 Day 7     Day 14  administration                                 ______________________________________                                        Ammonia  457     357       346   443                                          Phenol   18       5         4    17                                           Cresol   41      24        21    41                                           Indole   38      11         2    36                                           Skatole  16       4         2    13                                           ______________________________________                                    

Administration of lactulose decreased significantly the concentration oftoxic low molecule nitrides such as ammonia. 7 days after the end of theadministration, the concentration of those substances, however, returnedto the level prior to the administration.

Example 2

A daily dose of 16-24 mg of lactulose was administered orally to 33renal hemodialysis patients complaining of pruritus cutaneus for 8 weekscontinuously and their blood was collected in week 4 and week 8 for thedetermination of blood uremic toxins. The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Effect of lactulose on uremic toxins                                                      Week 0  Week 4    Week 8                                          ______________________________________                                        β.sub.2  microglobulin                                                                 25.6 ± 1.1                                                                           25.6 ± 1.3                                                                           26.5 ± 2.6                               (mg/l)                  (ns)      (ns)                                        Indole sulfate                                                                              33.1 ± 2.2                                                                           29.8 ± 2.2                                                                           27.6 ± 2.7                               (μg/ml)              (-10.0% ‡)                                                                   (-16.5% ‡‡)           p-Cresol (μg/ml)                                                                         7.66 ± 0.6                                                                           6.82 ± 0.7                                                                           6.35 ± 0.9                                                       (-10.9% ‡)                                                                   (-17.0% ‡)                       Phenol (μg/ml)                                                                           1.76 ± 0.3                                                                           1.73 ± 0.3                                                                           1.56 ± 0.3                                                       (ns)      (ns)                                        Methylguanidine                                                                             4.57 ± 0.3                                                                           4.03 ± 0.4                                                                           3.96 ± 0.3                               (nMOL/ml)               (-11.7% ‡‡)                                                       (-13.4% ‡‡)           Guanidinosuccinic                                                                           21.4 ± 1.8                                                                           20.9 ± 1.9                                                                           18.6 ± 2.2                               acid (nMOL/ml)          (ns)      (-13.1% ‡‡)           Methylguadinine/                                                                            37.2 ± 2.1                                                                           32.5 ± 2.1                                                                           32.8 ± 1.8                               Creatinine (%)          (-12.6% ‡‡)                                                       (-11.8% ‡‡)           ______________________________________                                         Mean ± Standard Error                                                      ‡ p < 0.05                                                         ‡‡ p < 0.01                                        

Blood concentration of uremic toxins such as β₂ -microglobulin, indolesulfate, p-cresol, phenol, methylguanidine and guanidinosuccinic acid isextremely higher than that of healthy subjects but administration oflactulose significantly decreased indole sulfate, p-cresol,methylguanidine and guanidinosuccinic acid.

Example 3

Relation between the 4 substances, indole sulfate, p-cresol,methylguadinine and gudininosuccic acid that showed significant decreaseby administration of lactulose and effect on alleviation of prurituscutaneus was examined. Each case showed more than 10% decrease after theadministration. Relation between the number of uremic toxins decreasedand the rate of efficacy is shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Number of substances decreased and rate of efficacy                           in 25 cases showing alleviation of pruritus cutaneus                          Number of        Number of                                                                              Rate of                                                                              Number of                                                                            Rate of                               substances                                                                            Number of                                                                              effective                                                                              efficacy                                                                             ineffective                                                                          inefficacy                            decreased                                                                             cases    cases    (%)    cases  (%)                                   ______________________________________                                        4       7        7        100    0       0                                    3       6        6        100    0       0                                    2       8        6         75    2       25                                   1       10       6         60    4       40                                   0       0        0         0     2      100                                   ______________________________________                                    

Not a single substance but several substances combined together areconsidered to be responsible for induction of pruritus cutaneus, and themore the number of the substances was decreased by more than 10% byadministration of lactulose, the better pruritus cutaneus wasalleviated. This proves that decline in the blood concentration ofuremic toxins by administration of lactulose is effective on betteralleviation of pruritus cutaneus.

Example 4

After breakfast and dinner, a total of 16-24 g of lactulose wasadministered orally to the 33 renal hemodialysis patients complaining ofpruritus cutaneus for 8 weeks. According to the criteria for theseverity of pruritus cutaneus in 5 scores (extremely itchy, very itchy,itchy, slightly itchy, no symptom), the effect of administration oflactulose on pruritus cutaneus was determined and evaluated in 5 grades(remarkably effective, effective, slightly effective, unchanged andaggravated) by comparing the scores at the start of and after theadministration. The effect of lactulose on pruritus cutaneus and itschange with time are shown in Tables 4 and 5, respectively.

                  TABLE 4                                                         ______________________________________                                        Effect of lactulose on pruritus cutaneus                                                         Number                                                                              (%)                                                  ______________________________________                                        Remarkably effective (pruritus                                                                      1      3.0                                              cutaneus score improved by at                                                 least 3 grades)                                                               Effective (pruritus cutaneus                                                                       12      36.4                                             score improved by not more                                                    than 2 grades)                                                                Slightly effective (pruritus                                                                       12      36.4                                             cutaneus score improved by                                                    not more than 1 grade)                                                        Unchanged (pruritus cutaneus                                                                        8      24.2                                             score unchanged)                                                              Aggravated (pruritus cutaneus                                                                       0      0                                                score aggravated)                                                             ______________________________________                                    

Administration of lactulose alleviated itching in 75.8% of the prurituscutaneus patients.

                  TABLE 5                                                         ______________________________________                                        Change with time in effect of lactulose on                                    pruritus cutaneus                                                                        Severe pruritus                                                                          Light pruritus                                                     cutaneus patients                                                                        cutaneus patients                                                  (extremely itchy +                                                                       (itchy + slightly                                                  very itchy)                                                                              itchy)                                                  ______________________________________                                        Before       54.6%        9.0%                                                administration                                                                2 weeks after                                                                              27.3         27.3                                                administration                                                                4 weeks after                                                                              12.0         48.6                                                administration                                                                8 weeks after                                                                              13.6         50.0                                                administration                                                                ______________________________________                                    

The percentage of the severe pruritus cutaneus patients decreased from54.6% prior to the administration down to 12% and that of the lightpruritus cutaneus patients increased from 9.0% to 50% 4 weeks after thestart of administration of lactulose.

INDUSTRIAL APPLICABILITY

Oligosaccharides like, but not limited to, fructo-oligosaccharide,galactooligosaccharide, isomalto-oligosaccharide, malto-oligosaccharide,lacto-sucrose and xylo-oligosaccharide, in particular, disaccharidessuch as, but not limited to, lactulose, trehalose, rhamnose and lactitolare effective on the treatment of renal failure or its complicationsassociated with renal hemodialysis patients, especially, prurituscutaneus.

We claim:
 1. A method of treating pruritus cutaneus resulting fromhemodialysis, comprising administering to a patient in need thereof, atherapeutically effective amount of a pharmaceutical composition in unitdosage form consisting essentially of at least one oligosaccharide asthe active ingredient, and a pharmaceutically acceptable excipient.
 2. Amethod of treating pruritus cutaneus resulting from renal failure,comprising administering to a patient in need thereof, a therapeuticallyeffective amount of a pharmaceutical composition in unit dosage formconsisting essentially of at least one oligosaccharide as the activeingredient, and a pharmaceutically acceptable excipient.
 3. The methodas claimed in claim 2 wherein said oligosaccharide is selected from thegroup consisting of fructo-oligosaccharide, galacto-oligosaccharide,isomalto-oligosaccharide, malto-oligosaccharide, lacto-oligosaccharide,xylo-oligosaccharide and mixtures thereof.
 4. The method as claimed inclaim 2 wherein said at least one oligosaccharide is a disaccharide. 5.The method as claimed in claim 4 wherein said disaccharide is selectedfrom the group consisting of lactulose, trehalose, rhamnose, lactitoland mixtures thereof.
 6. The method as claimed in claim 4 wherein saiddisaccharide is lactulose.
 7. A treatment method for amelioratingpruritus cutaneus resulted from hemodialysis, in a patient in need ofsaid treatment, comprisingadministering a pharmaceutical composition tosaid patient in an amount effective to provide said amelioration, saidpharmaceutical composition consisting essentially of, as an activeingredient, at least one oligosaccharide, and a pharmaceuticalexcipient, said pharmaceutical composition being present in a unitdosage form containing an amount of said at least one oligosaccharidesufficient for improving said pruritus cutaneus.